SCOTTSDALE, ARIZ. (FRONTLINE MEDICAL NEWS) – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans ( J Clin Psychiatry. 2007 May;68[5]:711-20 ), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

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